ArticleAmerican journal of human genetics2019
Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed.
- Clinical consensus guidelines for the management of Noonan syndrome in Japan.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2026Article
- Unveiling the Prevalence and Surgical Burden of Neurocristopathies: A Scoping Review and Statistical Analysis.Research square · 2026Article
- A Rras2-BMPR2 feedback loop sustains osteogenesis and represents a therapeutic target for osteoporosis.Nature communications · 2026Article
- Cell-type specific allelic dampening of sex-linked genes in sex chromosome aneuploidy.bioRxiv : the preprint server for biology · 2026Article
- De Novo RRAS2 Pathogenic Variant in a Fetus With Bilateral Radial Ray and Multisystem Anomalies.Prenatal diagnosis · 2026Article
- Genome wide association study of a Circadian Imbalance Index in 312,935 European ancestry UK Biobank participants identifies loci related to diabetes, mood and myocardial infarction.Research square · 2025Article
- Using modified mRNA for cardiomyocyte proliferation and cardiac genetic disease modelling and treatment.Biochemical Society transactions · 2025Review
- Ras-related protein 2 limits vascular smooth muscle cell phenotypic switching and abdominal aortic aneurysm development.Nature communications · 2025Article
- Broad Electrocardiogram Syndromes Spectrum: From Common Emergencies to Particular Electrical Heart Disorders-Part II.Diagnostics (Basel, Switzerland) · 2025Review
- Health outcomes and drug utilisation in children with Noonan syndrome: a European cohort study.Orphanet journal of rare diseases · 2025Article
- Mechanisms of brain overgrowth in autism spectrum disorder with macrocephaly.Frontiers in neuroscience · 2025Review
- Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.Nature genetics · 2024Article
- Severe generalized edema in a premature neonate: A case report and literature review.Clinical case reports · 2024Article
- RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.Disease models & mechanisms · 2024Review
- Article
- The ancestral type of the R-RAS protein has oncogenic potential.Cellular & molecular biology letters · 2024Article
- Construction and validation of a diagnostic model for rheumatoid arthritis based on mitochondrial autophagy-related genes.Heliyon · 2024Article
- Fast and slow muscle fiber transcriptome dynamics with lifelong endurance exercise.Journal of applied physiology (Bethesda, Md. : 1985) · 2024Article
- Identification of a novel frameshift variation in ANKRD11: a case report of KBG syndrome.Frontiers in genetics · 2024Article
- Functional analysis ofFrontiers in genetics · 2024Article
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33 authors.
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Abstract
Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.
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